1. Field of Invention
The present invention relates to .gamma.-diketone compound derivatives having inhibitory activity against platelet aggregation and pharmaceutical compositions useful for the treatment and prevention of thrombotic diseases.
2. Background Art
Cardiovascular diseases are increased along with the change of dietary habits and the increase of advanced ages. Almost fifty percent of these diseases may be caused by thrombus.
Platelets in plasma are mainly associated with the formation of thrombus in organisms. For the purpose of the treatment and prevention of thrombotic diseases in clinical practice, there have been used a medicine which suppresses the functions of platelet or inhibits the aggregation of platelets, for example, aspirin which inhibits cyclooxygenase and ticlopidine which activates adenylcyclase.
In recent years, glycoproteins on platelet membrane have been progressively studied. As a result, it has been elucidated that the membrane glycoprotein called GPIIb/IIIa is a receptor of fibrinogen. This has therefore led to the expectation that a GPIIb/IIIa antagonist would become an inhibitor of platelet aggregation having a novel action mechanism effectively used for the treatment and prevention of the thrombotic diseases (Trends in Pharmacological Science, 13, 413, 1992).
The compounds as the GPIIb/IIIa antagonist include, for examples, monoclonal antibodies (Ann. New York Acad. Sci., 614, 193, 1991), tripeptide derivatives comprising arginine-glycine-aspartic acid (J. Med. Chem., 35, 2040, 1992), amidinophenyl derivatives (J. Med. Chem., 35, 4393, 1992; Japanese Patent Laid-Open Publication Nos. 264068/1992, 334351/1992, EP-A-483667, EP-A-502536, EP-A-525629, EP-A-529858, EP-A-537980, WO-9307867 and WO-9402472), tyrosine derivatives (J. Med. Chem., 35, 4640, 1992), and piperidine derivatives (EP-A-512831, EP-A-540334 and EP-A-578535).
Further, for .gamma.-diketone compounds, compounds having a peptide bond are known in the art (Japanese Patent Laid-Open Publication No. 235853/1990, W09307867 and the like), whereas no compounds free from a peptide bond are known in the art. It is expected that such compounds not having any peptide bond are less likely to be metabolized by peptidases in vivo. Therefore, they are potentially promissing compounds which can offer prolonged duration of efficacy.
On the other hand, the development of a drug, not having side effects such as hemorrhage and with a highly selective function, as a therapeutic or preventive agent of thrombotic diseases has been desired in the art.